Di(4-chloro-phenyldiguanido) derivative which is free of potential genotoxicity and a process for reducing the residual amount of p-chloroaniline in said di(4-chloro-phenyldiguanido) derivative

Abstract

The invention relates to a process for reducing the residual amount of p-chloroaniline in chlorhexidine. Also, the invention relates to a process for preparing chlorhexidine, or a pharmaceutically acceptable salt thereof, which is free of potential genotoxicity. In addition, the invention refers to the said chlorhexidine, or a pharmaceutically acceptable salt thereof, which is free of potential genotoxicity. Further, the invention relates to an analytical HPLC method for the determination of potentially genotoxic impurities in samples of chlorhexidine, or of a pharmaceutically acceptable salt thereof. The invention also relates to stabilized chlorhexidine digluconate salt free of potential genotoxicity in aqueous solution, and to a method for stabilizing chlorhexidine digluconate salt free of potential genotoxicity in aqueous solution.

1 . Chlorhexidine, (compound of formula I), 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, which is free of potential genotoxicity, and wherein the said chlorhexidine, or a pharmaceutically acceptable salt thereof, has a concentration of equal to or less than about 40-50 ppm with respect to chlorhexidine, by HPLC, of p-chloroaniline (compound of formula III), 
       
       
         
           
           
               
               
           
         
       
     
     
         2 . The chlorhexidine, or a pharmaceutically acceptable salt thereof, of  claim 1 , which has a content of equal to or less than 0.15% of percentage area by HPLC of each of the compounds of formula IV, 
       
         
           
           
               
               
           
         
         wherein X is NH or O, and R is H, a carboxamidino group, or a carboxamido group. 
       
     
     
         3 . The chlorhexidine, or a pharmaceutically acceptable salt thereof, of  claim 2 , wherein the compound of formula (IV) is selected from the group consisting of compounds B-G, 
       
         
           
           
               
               
           
         
       
     
     
         4 . The chlorhexidine, or a pharmaceutically acceptable salt thereof, of  claim 1 , which is the mono- or diacetate salt, the mono- or dihydrochloride salt, or the mono- or digluconate salt of chlorhexidine. 
     
     
         5 . A pharmaceutical composition comprising the chlorhexidine or a pharmaceutically acceptable salt thereof as defined in  claim 1 , together with at least one pharmaceutically carrier and/or with at least one additional active pharmaceutical ingredient. 
     
     
         6 . The pharmaceutical composition of  claim 5 , wherein the at least one pharmaceutically acceptable carrier is benzalkonium chloride, menthol, ethanol, water, or mixtures thereof, and wherein the at least one additional active pharmaceutical ingredient is benzocaine, tirotricine, lidocaine, enoxolone, or mixtures thereof. 
     
     
         7 .- 29 . (canceled) 
     
     
         30 . The chlorhexidine, or a pharmaceutically acceptable salt thereof, of  claim 2 , which is the mono- or diacetate salt, the mono- or dihydrochloride salt, or the mono- or digluconate salt of chlorhexidine. 
     
     
         31 . The chlorhexidine, or a pharmaceutically acceptable salt thereof, of  claim 3 , which is the mono- or diacetate salt, the mono- or dihydrochloride salt, or the mono- or digluconate salt of chlorhexidine. 
     
     
         32 . A pharmaceutical composition comprising the chlorhexidine or a pharmaceutically acceptable salt thereof as defined in  claim 2 , together with at least one pharmaceutically carrier and/or with at least one additional active pharmaceutical ingredient. 
     
     
         33 . The pharmaceutical composition of  claim 32 , wherein the at least one pharmaceutically acceptable carrier is benzalkonium chloride, menthol, ethanol, water, or mixtures thereof, and wherein the at least one additional active pharmaceutical ingredient is benzocaine, tirotricine, lidocaine, enoxolone, or mixtures thereof. 
     
     
         34 . A pharmaceutical composition comprising the chlorhexidine or a pharmaceutically acceptable salt thereof as defined in  claim 3 , together with at least one pharmaceutically carrier and/or with at least one additional active pharmaceutical ingredient. 
     
     
         35 . The pharmaceutical composition of  claim 34 , wherein the at least one pharmaceutically acceptable carrier is benzalkonium chloride, menthol, ethanol, water, or mixtures thereof, and wherein the at least one additional active pharmaceutical ingredient is benzocaine, tirotricine, lidocaine, enoxolone, or mixtures thereof. 
     
     
         36 . A pharmaceutical composition comprising the chlorhexidine or a pharmaceutically acceptable salt thereof as defined in  claim 4 , together with at least one pharmaceutically carrier and/or with at least one additional active pharmaceutical ingredient. 
     
     
         37 . The pharmaceutical composition of  claim 36 , wherein the at least one pharmaceutically acceptable carrier is benzalkonium chloride, menthol, ethanol, water, or mixtures thereof, and wherein the at least one additional active pharmaceutical ingredient is benzocaine, tirotricine, lidocaine, enoxolone, or mixtures thereof. 
     
     
         38 . A pharmaceutical composition comprising the chlorhexidine or a pharmaceutically acceptable salt thereof as defined in  claim 30 , together with at least one pharmaceutically carrier and/or with at least one additional active pharmaceutical ingredient. 
     
     
         39 . The pharmaceutical composition of  claim 38 , wherein the at least one pharmaceutically acceptable carrier is benzalkonium chloride, menthol, ethanol, water, or mixtures thereof, and wherein the at least one additional active pharmaceutical ingredient is benzocaine, tirotricine, lidocaine, enoxolone, or mixtures thereof. 
     
     
         40 . A pharmaceutical composition comprising the chlorhexidine or a pharmaceutically acceptable salt thereof as defined in  claim 31 , together with at least one pharmaceutically carrier and/or with at least one additional active pharmaceutical ingredient. 
     
     
         41 . The pharmaceutical composition of  claim 40 , wherein the at least one pharmaceutically acceptable carrier is benzalkonium chloride, menthol, ethanol, water, or mixtures thereof, and wherein the at least one additional active pharmaceutical ingredient is benzocaine, tirotricine, lidocaine, enoxolone, or mixtures thereof.